As giant cell tumors occurring in a bone and soft tissue, there are known osteoclastoma occurring in a bone (giant cell tumor of bone, henceforth referred to as “GCTB”), giant cell tumor of tendon sheath-localized type occurring in a soft tissue (henceforth referred to as “GCTT”), pigmented villonodular synovitis (henceforth referred to as “PVNS”), and the like. In this specification, GCTB, GCTT, and PVNS are collectively referred to as giant cell tumors. In general, among the giant cell tumors, especially the giant cell tumor of tendon sheath (GCTT) and the pigmented villonodular synovitis (PVNS) may be generically named giant cell tumors of tendon sheath. In this specification, the term giant cell tumor of tendon sheath refers to the giant cell tumor of tendon sheath-localized type (GCTT) in a narrow sense, and for referring to the giant cell tumors of tendon sheath in a broad sense, the term tenosynovial giant cell tumors is used.
As a tumor occurring in a bone and soft tissue, chondrosarcoma is also known. Similarly, as a malignant tumor primarily occurring in a bone tissue, bone sarcoma is known.
Giant cell tumor of bone (GCTB) is a benign tumor frequently occurring in circumferences of the knee joints of young to middle- or advanced-aged persons, and accounts for 3 to 8% of the primitive bone tumors, and 15 to 20% of benign bone tumors. The morbidity of the giant cell tumor of bone (GCTB) is slightly higher in women, and patients' man-and-woman ratio is 1:1.3 to 1.5. Giant cell tumor of bone (GCTB) frequently occurs in 20 to 45 years old persons, and it is said that about 150 persons newly develop this disease in every year in Japan. Giant cell tumor of bone (GCTB) accounts for about 5% of all bone tumors, and about 20% of benign bone tumors.
As for occurring positions of giant cell tumor of bone (GCTB), it frequently occurs in long tubular bones, and it occurs in a distal end of the thighbone (namely, just above the knee) or a proximal end of the tibia (namely, just below the knee) in approximately half of the total cases. Next to these positions, giant cell tumor of bone (GCTB) frequently occurs at a distal end of the radius (namely, the jointing position of the thumb on the radius, which is the bone on the side of the thumb among the two bones connecting the elbow and the wrist), a proximal end of the humerus (namely, just under the shoulder), and the sacrum (namely, the inverse triangle bone near the inferior extremity of the backbone, locating at the center of the pelvis), which are mentioned in the descending order of occurring frequency. There are no symptoms peculiar to giant cell tumor of bone (GCTB), and the subjective symptoms are such nonspecific symptoms as a pain of affected part due to microfracture caused by reduction of bone strength, spontaneous pain, load-bearing pain, swelling, sense of heat, and difficulty in moving joint.
Although giant cell tumor of bone (GCTB) is classified as benign tumor, it shows characteristics between those of malignant and benign tumors, such as high proliferation velocity and high recurrence rate of 10 to 30%. In several percents of the cases of giant cell tumor of bone, it metastasizes to the lung within 1 to 10 years, and 25% of such patients die from proliferation of the tumor. Giant cell tumor of bone (GCTB) may rarely convert into highly malignant sarcoma, and it is reported that, as for the prognosis of such cases, five-year survival rate of such patients treated with chemotherapeutic treatment and extensive resection was 50%.
Since giant cell tumor of bone occurring before stop of increase of body height due to closing of the epiphyseal plate, or giant cell tumor of bone found at an early stage exists at the metaphysis (namely, an end part of diaphysis of a long tubular bone locating on the diaphysis side with respect to the epiphysis constituting a part of joint), it is fundamentally considered to be a tumor that occurs in the metaphysis and quickly infiltrates in the epiphysis. Hyperplasia of multinucleated giant cells and monocyte cells constitutes the major part of the pathological findings, and spindle cells are observed between them. The morphology and functions of the multinucleated giant cells are similar to those of osteoclasts. It is thought that the body of the tumor of giant cell tumor of bone consists of spindle cells similar to fibroblasts and osteoblasts existing in the stroma, and the multinucleated giant cells and monocyte cells are cells gathering in response to a cytokine produced by the tumor cells. Although it is considered that giant cell tumor of bone is probably a tumor originating in undifferentiated mesenchymal cells in the bone marrow, cell origin thereof is unknown.
There is only ablative operation as the radical therapy of giant cell tumor of bone (GCTB). In usual ablative operations, phenol treatment, alcohol treatment, zinc chloride treatment, freezing with liquid nitrogen, and thermotherapeutic treatment using heat of polymerization of methyl methacrylate bone cement are performed after curettage or excision of the lesion, for the purpose of annihilating remaining tumor cells to prevent recurrence, and the recurrence rate of 30 to 50% observed without such treatments as mentioned above is thereby successfully lowered to 10 to 25%.
Although it is rare for giant cell tumor of bone (GCTB) to follow a fatal process, it is a disease of which repetition of recurrence gradually spoils motor functions of bones and joints, and at the same time, for which surgical operations cause nerve damages to greatly degrades the quality of life, and therefore there is desired a therapeutic treatment that is not based on surgical operation, but on an internal medical therapeutic treatment, and does not invite recurrence or metastases to the lung.
As for a therapeutic treatment for giant cell tumor of bone (GCTB) not based on surgical operation, there is investigated application to giant cell tumor of bone of denosumab (trade name, Ranmark), which comprises an anti-RANKL human monoclonal antibody, and is clinically used as a therapeutic agent for bone diseases caused by multiple myeloma and bone diseases caused by solid carcinoma metastases. However, said medicament is a therapeutic agent aiming at suppressing the functions of the RANKL protein required for formation and activation of osteoclasts to prevent bone destruction, and is not a therapeutic agent aiming at suppressing tumor proliferation itself, and as for the administration route, it should be subcutaneously administered.
Therefore, there is desired a therapeutic agent for giant cell tumor of bone (GCTB) that can be orally administered, and can suppress tumor proliferation, per se. Giant cell tumor of tendon sheath (GCTT) is a soft tissue tumor that frequently occurs around joints and tendon sheaths at peripheries of arms and legs, and in particular, cases thereof developing the tumor adjacently to the tendon sheaths around interphalangeal joints of fingers are overwhelmingly frequently observed. Giant cell tumor of tendon sheath (GCTT) occurs around joints of fingers or on flexor tendons in about 85% of the cases, and it next frequently occurs in foot. Giant cell tumor of tendon sheath (GCTT) may infiltrate in bones. Although giant cell tumor of tendon sheath (GCTT) is synonymous with nodular tenosynovitis, but it is not an inflammatory disease, but it is a tumor. Although there is not known any report describing exact occurrence frequency of giant cell tumor of tendon sheath (GCTT), it is a disease of which number of cases is next to those of lipoma and neurilemmoma among benign soft tissue tumors that are excised by orthopedists for the purpose of therapeutic treatment, and it is not a rare disease. Giant cell tumors of tendon sheath (GCTT) frequently occurs in adults in their thirties to fifties, and especially frequently occurs in women, and the patients' man-and-woman ratio was reported to be 1:2. There are no special subjective symptoms of giant cell tumor of tendon sheath (GCTT), and it occurs as hypodermic tumor in fingers with no substantial pain, shows slow proliferation, and generally passes several years until it is diagnosed by a medical examination of a medical practitioner.
As the pathology of giant cell tumor of tendon sheath (GCTT), orbicular-ovate to spindle-shaped histiocyte-like monocytes showing diffusible proliferation and osteoclast-like multinucleated giant cells are intermingled in tumors showing clear borders. The cause of giant cell tumor of tendon sheath (GCTT) is unknown, and the origin of tumor cells is also unknown.
Giant cell tumor of tendon sheath (GCTT) is classified as benign tumor, and it seldom follows fatal process. However, it strongly tends to proliferate and spread over surroundings, and it recurs in 20 to 30% of the cases even if extirpation operations are conducted. Since giant cell tumor of tendon sheath (GCTT) strongly adheres to tendon sheath, it is hard to excise it, and if an extirpation operation is conducted, adhesion of extensor tendon or flexor tendon, and injury to nerves or blood vessels are easily caused. Moreover, advance of giant cell tumor of tendon sheath (GCTT) destroys bones, joints, and ligaments. Therefore, there is desired a therapeutic treatment of giant cell tumor of tendon sheath (GCTT) that is not based on surgical operation, but is based on an internal medical therapeutic treatment, and does not invite recurrence and metastasis to lung. There is also desired a therapeutic agent for giant cell tumor of tendon sheath (GCTT) that can be orally administered, and can suppress tumor proliferation.
Pigmented villonodular synovitis (PVNS) is a benign tumor that occurs in relatively young adults not older than 40, and slightly more frequently occurs in women. As for occurring position of PVNS, it most frequently occurs in the knee joint, and also frequently occurs in the large joints such as hip, leg, elbow, and shoulder joints, and surroundings thereof. PVNS is a disease that shows abnormal proliferation of tissues of the synovial membrane covering the inside of joints, forms tumors, and repeatedly causes hemorrhage. It is classified as that of “diffuse type” in which tumors are densely formed like piles of carpet on the whole surface, and “limited type (nodule type)” in which tumors are serially formed in a row, and the both types may simultaneously seen in not a few cases.
The subjective symptoms thereof include swelling and dull pain of joints, sticking sense of joints, disability for bending and extending joints beyond a certain extent, hot sensation at the knee, and the like, and blood often accumulates in joints.
PVNS is defined to be the same as the diffuse type giant cell tumor according to the WHO classification, and classified as a benign soft tissue tumor. In fact, tumors of PVNS themselves do not metastasize to other organs, and grow slowly, and therefore it is not a fatal disease. However, if PVNS is neglected, destruction and deformation of bones advance to cause gonarthrosis and greatly spoil the quality of life of patients, and therefore it is a disease for which an early treatment is required. Moreover, since PVNS infiltrates in a diffusive manner, complete excision thereof is difficult, and it recurs in about 50% of patients. As for histological characteristics, it shows diffusive proliferation of synovial cell-like monocytes, and there are intermingled osteoclast-like multinucleated giant cells, foam cells, siderophores, inflammatory cells, and the like. The cell origin of PVNS is unknown.
There is only ablative operation as the therapeutic treatment of PVNS. In ablative operation of PVNS, grown synovial membrane should be excised under observation with an endoscope or after incision of joint. However, even if the surgical operation is conducted so that neither the joint capsules nor the ligamentum tissues should be injured, if it infiltrates to a bone, it should also be eliminated by curettage, and depending on degree of infiltration to a bone, use of an artificial joint or amputation of leg or arm may be required.
Therefore, there is desired a therapeutic treatment that is not based on surgical operation, but is based on an internal medical therapeutic treatment. There is also desired a therapeutic agent for PVNS that can be orally administered, and can suppress tumor proliferation.
As described above, for all of giant cell tumor of bone, giant cell tumor of tendon sheath, and PVNS, any effective therapies have not been developed at present, except for surgical operation.
Chondrosarcoma accounts for about 20% of primary malignant bone tumors, and is a malignant tumor showing the secondly highest occurrence frequency following that of bone sarcoma. It occurs in persons of such a broad age range as twenties to sixties, and it is comparatively frequently observed in, in particular, persons of middle or advanced age of 40 years old or older, and such cases account for almost half of the total cases. As for the patient's man-to-woman ratio, chondrosarcoma occurs about twice frequently in men compared with women.
As for onset position of chondrosarcoma, it frequently occurs in the thighbone (namely, the bone of thigh above knee), humerus (namely, the bone extending from elbow to shoulder), pelvis, rib, scapula, and flat bone, and the cases occurring in these positions account for 70 to 80% of the total cases.
As for the subjective symptoms of chondrosarcoma, patients frequently notice the disease from swelling of affected part or dyskinesia, patients may also notice the disease from hard tumor giving weak pain, and pain caused by bone fracture. Histological images of chondrosarcoma show abundant glasslike cartilage matrices or mucous matrices, and they proliferate in a lobulating shape. Histological images of chondrosarcoma generally present (1) abundant cell components, (2) hypertrophy of nuclei, (3) appearance of hypertrophied binucleated cells, (4) appearance of chromatin-abundant multinucleated giant cartilage cells, and the like. Although the borders of tumors of chondrosarcoma are comparatively clear, there is observed infiltration thereof between bone trabeculae (namely, finely loosen part of the spongin tissues at the epiphysis of a long tubular bone), or in the Havers canal (namely, passage of blood vessels locating at the center of bone lamella system of the compact bone in the diaphysis of a long tubular bone). The cause and cell origin of chondrosarcoma are unknown.
As the radical therapy of chondrosarcoma, there is only ablative operation. Against chondrosarcoma, effect of radiotherapy or anticancer drug treatment is not sufficient. Since chondrosarcoma is a malignant tumor, extensive excision is performed so as to excise the tumor and surrounding tissues together with covering normal tissues. Therefore, the surgical operation involves a risk of spoiling motor functions, and amputation of diseased limb is sometimes unavoidable. Although the five-year survival rate of chondrosarcoma is 70 to 80%, there are not a few cases where a long-term process of ten years or longer including repetitive recurrences results in death.
Therefore, there is desired a therapeutic treatment of chondrosarcoma that is not based on surgical operation, but is based on an internal medical therapeutic treatment. There is also desired a therapeutic agent for chondrosarcoma that can be orally administered, and can suppress the tumor proliferation.
Bone sarcoma is a malignant tumor that primarily develops in a bone tissue, and is a malignant tumor that directly produces osteoid (constituent element of bone tissues consisting of matrix and fibers), or bone. Bone sarcoma is the most frequently occurring tumor among the malignant tumors that primarily develop in a bone, and it occurs in 1 to 2 persons out of one million persons, and occurs in about 200 persons every year in Japan. Bone sarcoma patients in their teens account for 60%, and those in their twenties account for 15% of the total bone sarcoma patients. As for the patients' man-to-woman ratio, it slightly more frequently occurs in men compared with women. Bone sarcoma cases account for about 33% of the total cases of malignant tumors that primarily develop in bones.
Bone sarcoma frequently occurs in a long tubular bone, and the most frequently occurring positions are, from the highest frequency, the knee (distal position of the thighbone (namely, position above the knee) and proximal position of the tibia (namely, position below the knee), of which cases account for 60%, hip joint, of which cases account for 15%, shoulder joint, of which cases account for 10%, and jaw, of which cases account for 6%, and these frequencies are similar to the occurrence frequencies of the giant cell tumor of bone for such positions. As a subjective symptom of bone sarcoma, continuous pain arises, and such pain occurs in connection with sporting activities. Therefore, it may be mistaken for muscular pain, and thus cautions are required.
Although the five-year survival rate of bone sarcoma depends on medical facilities, there is a report that it was about 70% for the cases without metastasis. Bone sarcoma frequently metastasizes to the lung, like giant cell tumor of bone. Prognosis of the cases for which metastasis is found at the time of the first medical examination is bad, and the five-year survival rate for such cases is about 20% even in advanced facilities.
In the histopathological sense, bone sarcoma is a low differentiation spindle-shaped multinucleated sarcoma. However, histological images thereof show a wide variety of aspects, including from those apparently seen only as reactive osteogenesis or fibrosis to those showing consolidation with marked bone and osteoid formation, those showing marked chondrogenesis, as well as those showing characteristics of utterly undifferentiated sarcoma hardly accompanied by osteoid, and thus considerably change, and it always appears in different ways depending on positions even in the same tumor. Appearance of multinucleated giant cells almost always observed, and they show various appearances both in amount and quality, including those of osteoclast-like gentle type to those of strange appearance apparently seen to be malignant, and may sometimes show giant cell tumor of bone-like images.
As therapies of bone sarcoma, chemotherapeutic treatment and surgical operation are mainly conducted. The chemotherapeutic treatment for bone sarcoma is characterized in that the chemotherapeutic treatment is performed in advance of surgical operation, unlike those for the other types of cancers. Already existing invisible micrometastases (lung, liver, bone, and the like) can be thereby eradicated or suppressed, and an effective anticancer agent can also be thereby determined. Therefore, it enables selection of anticancer agent to be used in postoperative chemotherapeutic treatment (performed after surgical operation), or chemotherapeutic treatment to be performed at the time of recurrence. At present, cisplatin, adriamycin, ifosfamide, cyclophosphamide, ethoposide, methotrexate, doxorubicin, bleomycin, and caffeine are frequently used in an appropriate combination thereof. For example, in the caffeine-combined therapy, cisplatin, adriamycin, and caffeine are used in combination. Most of these anticancer agents should be administered by drip infusion.
The most important in topical treatment of bone sarcoma is to surely excise the primary lesion. However, considering the frequent occurrence in young persons, preservation of motor functions is also important. The number of cases not requiring amputation of leg or arm, and allowing preservation of the diseased limb is increasing in recent years. However, if an artificial joint must be used, lifetime of artificial joint is about 20 years, and therefore there arises a problem that, even if the disease is completely cured, a resurgical operation is required for replacing the artificial joint.
Therefore, there is desired a therapeutic agent for bone sarcoma that can be orally administered, and can suppress proliferation of bone sarcoma cells. There is also desired a therapeutic agent for bone sarcoma that can suppress metastasis of bone sarcoma cells to the lung.
As described above, giant cell tumor of bone (GCTB), giant cell tumor of tendon sheath (GCTT), pigmented villonodular synovitis (PVNS), chondrosarcoma, and bone sarcoma are tumors that occur in bone soft tissues, and they are commonly characterized in that there are no radical therapy other than ablative operation, and even if ablative operation is conducted, repetitive recurrence continuously degrades the quality of life of patients. However, the causes and original cells thereof are unknown. Although histologically osteoclast-like multinucleated giant cells are commonly observed in giant cell tumor of bone (GCTB), giant cell tumor of tendon sheath (GCTT), PVNS, and bone sarcoma, it is estimated that the body of the tumor is not the osteoclast-like multinucleated giant cells, and therefore there are of course not known any therapeutic treatment based on a mechanism commonly applicable to giant cell tumor of bone (GCTB), giant cell tumor of tendon sheath (GCTT), pigmented villonodular synovitis (PVNS), and chondrosarcoma, and any attempts for developing medicaments for such therapeutic treatment.
As report concerning therapeutic agent for giant cell tumor occurring in bones and soft tissues known so far, there is only a report that mizoribine, which is an immunosuppressant based on inhibitory action against the biosynthesis system of purine of nucleic acids, slightly inhibited proliferation of PVNS in vitro (Patent document 1), except for the reports of the inventors of the present invention themselves. The reports of the inventors of the present invention, to which the provisions of the exception to loss of novelty or grace period shall be applied, are not mentioned in this section as prior art references.
The peroxisome proliferator-activated receptor γ (PPARγ) is a transcriptional factor protein belonging to the intranuclear receptor superfamily, which exists in fat cells, macrophages, and the like. PPARγ exists as a hetero-complex formed together with the retinoid X receptor (RXR) protein.
It is considered that, in the absence of a PPARγ agonist, the hetero-complex of PPARγ and RXR binds with a corepressor protein complex, and binds to the PPAR response element (PPRE) existing in a promoter region of a lipid metabolism-related gene in a genome gene to suppress transcription of mRNAs of the genes existing downstream thereof, including apoptosis-related genes, various lipid metabolism-related genes or fat cell differentiation-related genes such as those for lipoprotein lipase (LPL) and fatty acid transport protein (FATP), arteriosclerosis-related genes, and anti-inflammation-related genes. It is also considered that, however, if a PPARγ agonist binds to PPARγ, a co-activator protein complex binds to the hetero-complex of PPARγ and RXR in place of release of the co-repressor protein complex from the hetero-complex of PPARγ and RXR to promote transcription of mRNAs of the genes existing downstream from the PPAR response element (PPRE), including the apoptosis-related genes, various lipid metabolism-related genes or fat cell differentiation-related genes such as those for lipoprotein lipase (LPL) and fatty acid transport protein (FATP), arteriosclerosis-related genes, and anti-inflammation-related genes.
As PPARγ agonists, there are known angiotensin II receptor antagonists such as irbesartan and telmisartan, thiazolidinedione derivatives, non-steroidal anti-inflammatory agents, and endogenous ligands such as 15-deoxy-Δ12,14-prostagladin J2 (15d-PGJ2), 15-hydroxyeicosatetraenoic acid (15-HETE), 9-hydroxyoctadecadienoic acid (9-HODE), 13-hydroxyoctadecadienoic acid (15-HODE), nitrolinoleic acid, oxidized LDL, long chain fatty acids, eicosanoids, and lysophospholipids. Long chain fatty acid refers to an aliphatic acid containing 11 or more carbon atoms in the molecule.
The angiotensin II receptor antagonists are agents for lowering blood pressure by inhibiting binding of angiotensin II, which is a pressor substance, with the receptor thereof. Irbesartan and telmisartan are angiotensin II receptor antagonists currently used on clinical sites, and they are known to have a partial agonistic activity for PPARγ (partial agonist), in addition to the angiotensin II receptor antagonist activity.
There is not known any prior art reference describing that an angiotensin II receptor antagonist can be used for prophylactic or therapeutic treatment, or prevention of metastasis of giant cell tumor occurring in bones and soft tissues, chondrosarcoma, or bone sarcoma.
The thiazolidinedione derivatives are known as therapeutic agents for type II diabetes mellitus, and pioglitazone and rosiglitazone are clinically used. The thiazolidinedione derivatives exhibit activities for improving insulin resistance, suppressing saccharide production in the liver, promoting saccharide incorporation in peripheral cells, combusting fatty acids, promoting sensitivity of insulin receptor, suppressing arteriosclerosis, anti-inflammation, suppressing myocardial hypertrophy, and the like by eliminating hypertrophied fat cells that secrete TNFα, resistin, MCP-1, PAI-1, and the like by apoptosis, or deriving them to differentiate into small fat cells that secrete adiponectin into blood.
As the thiazolidinedione derivatives, there are known pioglitazone, rosiglitazone, troglitazone, isaglitazone, netoglitazone, rivoglitazone, balaglitazone, lobeglitazone, englitazone, ciglitazone, and the like. However, since they may cause critical adverse drug reaction, those clinically used at present as therapeutic agent for type II diabetes mellitus are only pioglitazone and rosiglitazone.
In addition to the activity as a therapeutic agent for type II diabetes mellitus, the thiazolidinedione derivatives such as pioglitazone are known on a laboratory level to inhibit proliferations of colon cancer (Non-patent documents 1 and 2), gastric cancer (Non-patent documents 3 and 4), non-small cell type lung cancer cells (Non-patent document 5), chondrosarcoma (Non-patent document 6), and malignant melanoma (Non-patent document 7). It is also known that thymoquinone having anticancer activity increases the PPARγ activity in breast cancer cells (Non-patent document 8).
Besides the above, Japanese Patent Unexamined Publication (Kokai) No. 2005-200419 (Patent document 2) describes, in the claims, a method for therapeutic treatment of cancer using a mevalonate pathway inhibitor and a PPARγ agonist in combination, but it does not mention any example at all. Therefore, it is an unverified invention, and does not have any meaning as a prior art. Similarly, Japanese Patent Unexamined Publication (Kohyo) No. 2009-533467 (Patent document 3) describes, in claims 9, and 14 to 17, uses of compounds having the thiazolidinedione structure represented by a general formula for therapeutic treatment of carcinoma, sarcoma, and giant cell tumor of bone. However, like Patent document 2, it does not mention any example indicating the pharmacological activity at all.
As described above, there are not known any prior art references describing that thiazolidinedione derivatives can be used for prophylactic and therapeutic treatments, or prevention of metastasis of giant cell tumor occurring in bones and soft tissues with scientific evidences, except for the reports of the inventors of the present invention themselves.
The non-steroidal anti-inflammatory agents are non-steroidal agents having anti-inflammatory activity, analgesic action, and antipyretic action, of which typical example is aspirin (namely, acetylsalicylic acid), and they are known as relatively safe drugs. It is known that, as for the action mechanism of the non-steroidal anti-inflammatory agents, they provides the anti-inflammatory activity, analgesic action, and antipyretic action through inhibitory activity against cyclooxygenase 1 and/or cyclooxygenase 2.
As the non-steroidal anti-inflammatory agents, there are known zaltoprofen, diclofenac, indomethacin, proglumetacin, indometacin farnesil, celecoxib, etodolac, meloxicam, mofezolac, acemetacin, oxaprozin, acetaminophen, lornoxicam, ampiroxicam, piroxicam, naproxen, loxoprofen, rofecoxib, ethenzamide, diflunisal, aluminoprofen, nahumetone, ketoprofen, acetylsalicylic acid, ibuprofen, pranoprofen, sulindac, and the like, and various kinds of drugs are widely used on clinical sites as drugs for ameliorating such symptoms as headache, toothache, menstrual pain, and pyrexia.
Proglumetacin and maleate thereof are prodrugs that are metabolized into indomethacin in the body and exhibit the efficacy. Similarly, indometacin farnesil is a prodrug that is metabolized into indomethacin in the body and exhibits the efficacy. Similarly, ampiroxicam is a prodrug that is metabolized into piroxicam in the body and exhibits the efficacy.
As for use of non-steroidal anti-inflammatory agents for oncotherapy, Japanese Patent Unexamined Publication (Kokai) No. 2005-343802 (Patent document 4) describes in the examples that when ketoprofen was transdermally administered to nude mice transplanted with the OST cells, which are human bone sarcoma-derived cultured cells, the tumor weight decreased to 48% of that observed in a placebo group after four weeks. Further, Japanese Patent Unexamined Publication (Kohyo) No. 2006-501136 (Patent document 5) describes methods for therapeutic treatments of pain, inflammation, cancer, Alzheimer's disease, and cardiovascular disease using a PPARγ agonist or selective inhibitor for cyclooxygenase 2 in the claims thereof. However, it does not describe at all any results of examples demonstrating the pharmacological actions.
As for prior art describing relation between PPARγ agonist and non-steroidal anti-inflammatory agent, it was reported that diclofenac or celecoxib prevented occurrence of colon cancer induced by repetitive administration of 1,2-dimethylhydrazine dihydrochloride to rats, and at the same time, these agents reduced amount of NF-κB protein in the large intestine, and increased amount of the PPARγ protein (Non-patent document 9).
As for action on synovial cells derived from rheumatism patients, it was reported that troglitazone, indomethacin, diclofenac, oxaprozin, and zaltoprofen activated PPARγ, and caused apoptosis to suppress proliferation of the cells, but NS-398, which is a selective cyclooxygenase 2 inhibitor, did not activate PPARγ and did not cause apoptosis, although it suppressed proliferation of the cells, and ketoprofen and acetaminophen did not cause activation of PPARγ, apoptosis, and suppression of the proliferation (Non-patent document 10).
Furthermore, it was reported by the inventors of the present invention that when zaltoprofen was allowed to act on giant cell tumor of bone (GCTB) derived from a patient, it suppressed proliferation of the cells of the giant cell tumor of bone, promoted expression of PPARγ in the cells of giant cell tumor of bone, and induced differentiation of the cells into fat cells (Non-patent documents 11 and 12).
Similarly, it was reported by the inventors of the present invention that when zaltoprofen or troglitazone was allowed to act on giant cell tumor of bone (GCTB) derived from a patient, these drugs suppressed proliferation of the cells of the giant cell tumor of bone, and promoted expression of PPARγ in the cells of giant cell tumor of bone, and zaltoprofen induced differentiation of the cells into fat cells (Non-patent documents 13, 14, 15, and 16).
It was also reported by the inventors of the present invention that in a patient who had taken zaltoprofen for four weeks at a dose of 240 mg per of day, which is the standard dose mentioned in the package insert, giant cell tumor of bone disappeared, but instead, fat cell-like cells showing enhanced expression of PPARγ were observed (Non-patent documents 13 and 17).
Similarly, it was also reported by the inventors of the present invention that zaltoprofen, pioglitazone, and troglitazone induced apoptosis in the cells of H-EMC-SS, which is a chondrosarcoma cell line, to suppress proliferation thereof, and promoted expression of PPARγ (Non-patent documents 18 and 19).
Non-patent documents 11 to 19 mentioned above, which are reports of the inventors of the present invention themselves, do not constitute prior arts of the present invention, since provisions of the exception to loss of novelty or grace period shall be applied to them.
As described above, except for the reports of the inventors of the present invention themselves, there are not known any prior art references describing that non-steroidal anti-inflammatory agents can be used for prophylactic treatment, therapeutic treatment, or prevention of metastasis of giant cell tumor occurring in bones and soft tissues, chondrosarcoma, or bone sarcoma.
Moreover, since it is not considered that there is any radical therapy for giant cell tumor occurring in bones and soft tissues except for ablative operation, and it is considered that the first priority of the treatment of chondrosarcoma or bone sarcoma is given to raising survival rate by extensive excision, an object of improving ability to carry out everyday activities of patients suffering from giant cell tumor occurring in bones and soft tissues, chondrosarcoma, or bone sarcoma is not recognized.